THROMBOSIS OF THE ARTERIAL AND CEREBRAL VASCULATURE: NEW MOLECULAR GENETIC
CONCEPTS FOR PREVENTION AND TREATMENT

Release Date:  April 15, 1999

RFA:  HL-99-015

P.T.

National Heart, Lung, and Blood Institute
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date: August 16, 1999
Application Receipt Date: September 15, 1999

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS RFA INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA.

PURPOSE

The objective of this initiative is to establish collaborative teams of closely
interacting investigators with diverse, complementary areas of expertise to
elucidate the molecular genetic mechanisms of thrombosis in the arterial and
cerebral vasculature.  The overall goal is to stimulate innovative
multidisciplinary research to expedite progress in understanding the pathogenesis
of thrombosis in both the arterial and cerebral vasculature and to facilitate the
application of new findings for better detection,  prevention, and treatment.

This initiative will support research to map and identify genes that confer
susceptibility to or protection from arterial thrombosis, to perform mechanistic
studies that will clarify the role of specific genetic alterations that lead to
or help prevent organ specific arterial thrombosis, and to apply and further
refine sophisticated molecular genetic methods and technologies, such as DNA
arrays, gene knock-outs, gene knock-ins, and gene alterations directed to
specific tissues at specific times in development.

In addition, this program will foster collaborations among scientists with
different expertise, abilities, and talents to solve problems that require a
multifaceted approach, diverse skills, and special resources (populations,
equipment, etc.) not typically located within a single department or at a given
institution.  The collaborations should focus on a common hypothesis with all
component projects contributing scientifically to the central theme.  The
collaborative projects may include shared resources as long as the
interdependence and multidisciplinary nature of the individual components is
demonstrated.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of Healthy People 2000, a PHS-led national
activity for setting priority areas.  This is related to the priority area, 
heart disease and stroke.  Potential applicants may obtain a copy of "Healthy
People 2000" (Full Report:  Stock No.017-001-00474-0 or Summary Report: Stock No.
017-001-00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State or local governments, and eligible agencies of the
Federal government.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

All current policies and requirements that govern the research grant programs of
the NIH will apply to grants awarded under this RFA.  Awards under this RFA to
foreign institutions will be made only for research of very unusual merit, need,
and promise, and in accordance with Public Health Service policy governing such
awards. Cell biology, molecular biology, biochemistry, physiology, pathology, and 
genetics are among the disciplines and expertise that may be appropriate for this
research program.

MECHANISM OF SUPPORT

The mechanism of support for applications in response to this RFA is the
collaborative Research Project (R01) grant.  Applicants should propose a program
comprising basic and/or clinical science studies.  Investigators are encouraged
to establish collaborations to complement their projects to meet the objectives
of  this RFA. Collaborative groups may consist of two or more research R01
projects consisting of basic science and/or clinical studies.  Collaborative
groups must have a common theme. Collaborative R01 projects may be from a single
institution or several institutions, may include shared resources, and should
demonstrate synergism among the individual components. If core support is
requested, it should be organized as a separate R01 application and submitted as
part of the collaboration, but its funding will be part of one of the research
R01s. The funding decision will be influenced by the scientific merit of the
individual applications, the degree of collaboration among the investigators, 
the approaches taken to meet the objectives of the RFA, and the programmatic
balance and needs of NHLBI and NINDS.  Although applicants are required to submit
collaborative applications, the Institute may choose to fund individual R01s
outside the collaborative arrangement owing to their special scientific merit and
programmatic needs and balance.

Specific application instructions have been modified to reflect "MODULAR GRANT"
and "JUST-IN-TIME" streamlining efforts being introduced by the NIH.  The modular
grant concept establishes specific modules in which direct costs may be requested
as well as a maximum level for requested budgets.  Only limited budgetary
information is required under this approach.  The just-in-time concept allows
applicants to submit certain information only when there is a possibility for an
award.  It is anticipated that these changes will reduce the administrative
burden for the applicants, reviewers and Institute staff.

For this RFA, funds must be requested in $25,000 direct cost modules. A feature
of the modular grant concept is that no escalation is provided for future years.
All anticipated expenses for all years of the project must be included within the
number of modules being requested.  If substantially increased costs are
anticipated in one or more of the future years, a full and complete justification
must be submitted with the application.  Only limited budget information will be
required and any budget adjustments made by the Initial Review Group will be in
modules of $25,000.

A group of collaborative R01 applications may request up to a total of 32 modules
($800,000 direct cost), per year for all component R01s, including cores.  Costs
of individual R01 components may be substantially different from each other
within a collaborative group.

Instructions for completing the Biographical Sketch have also been modified.  In
addition, Other Support information and the application Checklist page are not
required as part of the initial application.  If there is a possibility for an
award, necessary budget, Other Support and Checklist information will be
requested by NHLBI staff following the initial review.  The APPLICATION
PROCEDURES section of this RFA provides specific details of modifications to
standard PHS 398 application kit instructions.

This RFA is a one-time solicitation.  Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.  It is anticipated
that support for this program will begin in August 2000.  Administrative
adjustments in project period and/or amount may be required at the time of the
award.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1999, approximately $10 million total
costs will be available from the NHLBI and $2.3 million from NINDS for the first
year of support for this initiative.  Award of grants pursuant to this RFA is
contingent upon receipt of such funds for this purpose.  It is anticipated that
eight to ten collaborative groups will be funded. The specific number to be
funded will, however, depend on the merit and scope of the applications received
and on the availability of funds. Direct costs will be awarded in modules of
$25,000, less any overlap or other necessary administrative adjustments.
Facilities and Administrative costs (Indirect costs) will be awarded based on the
negotiated rates.

Applicants may request up to five years of funding.  A small number of programs
with well-justified needs for a research period of longer than five years may be
funded. A maximum of seven years can be requested in the case of studies in which
identification and study of individuals and families at risk for arterial
thrombosis are involved to allow sufficient time for development and testing of
protocols, ascertainment and recruitment, and data clean-up and analysis.  Other
types of studies should be completed in five years or less.  It is expected that
all components of a collaborative group will request the same length of funding.

RESEARCH OBJECTIVES

A. Background

Arterial thrombosis is the underlying mechanism responsible for myocardial
infarction, peripheral vascular occlusion, and most cases of non-hemorrhagic
cerebrovascular stroke as well as an important contributor to many other human
disorders central to the mission of the NHLBI and the NINDS.  Indeed, this
pathologic process represents the leading cause of mortality and morbidity in the
Western world.  Significant advances in the biochemistry and molecular biology
of the hemostatic system and the blood vessel wall as well as the pathophysiology
of arterial thrombotic disorders provide the underpinnings for rapid progress in
understanding the genetic abnormalities responsible for arterial thrombosis.
Moreover, these advances have led directly to improved therapy for thrombosis. 
The goal of this initiative is to speed the development of new treatment for
arterial thrombosis through promoting identification and characterization of
genes involved in the process.

The concept of a "hypercoagulable state" in which the hemostatic system is in a
state of enhanced but sub-thrombotic activity is supported by a number of large
epidemiologic studies.  The relationship between hemostatic abnormalities and
arterial thrombosis in coronary heart disease as well as cerebrovascular stroke
has been established.  For example, individuals with high levels of fibrinogen,
von Willebrand Factor VIIIc, and tissue plasminogen activator/tissue plasminogen
activator inhibitor-1 exhibit an increased risk of arterial thrombosis. 
Polymorphisms of certain hemostatic factor genes may be correlated with increased
levels of these components, as well as with the arterial thrombotic phenotype as
evidenced by the recent reported link between polymorphisms in the coagulation
factor VII gene to the risk of myocardial infarction.  Until now, it has been
believed that genetic mutations important for the prediction of venous thrombosis
such as factor V Leiden and antithrombin III are not relevant in arterial
thrombosis.  However, a newly described mutation in the prothrombin gene is
reported to be a risk factor for both venous and arterial thrombosis. 
Measurements of coagulation system activation fragments and enzyme-inhibitor
complexes are also correlated with the arterial thrombotic phenotype.  It remains
unclear whether the relatively small alterations in the levels/activities of
hemostatic components contribute to more extensive arterial thrombosis or whether
these abnormalities merely reflect underlying blood vessel wall dysfunction that
is responsible for the increased risk of this disorder.  Furthermore, it has not
yet been demonstrated that these small alterations are predictive of arterial
thrombotic disease in any specific individual.

We now understand fluid phase blood coagulation in considerable detail. These
advances in understanding have led directly to new anti-coagulants of
considerable potential value in the treatment of venous thrombosis.  However,
further advances beyond anticoagulation are required to provide effective
prophylaxis and therapy of arterial thrombosis.  This may be because cellular
components such as platelets and leukocytes play a more central role in the
process.  Fundamental research, supported by the NHLBI, has led to a new
generation of anti-arterial thrombotics based on inhibition of platelet
glycoprotein IIb-IIIa.  These agents along with other anti-platelet agents are
of proven value in this process.  Our understanding of platelet adhesive events
are somewhat less advanced than blood coagulation, primarily because the key
components have only recently been identified.  Furthermore, the adhesive events
are under the control of complex intracellular signaling pathways.  In contrast
to blood coagulation, many of the components of these pathways have yet to be
identified. In addition, polymorphisms in platelet adhesion receptors may be
directly linked to the risk of arterial thrombosis.  For example, the PLA2
polymorphisms in GP IIb-IIIa have  been implicated in myocardial infarction. 
Further, there is wide individual variation in the expression of a collagen
receptor, integrin à2þ1, on platelets.  This hereditary variation may also
correlate with the risk for myocardial infarction. Since there are many
unidentified gene products involved in regulating platelet adhesive interactions,
the identification of such gene products should provide candidate genes for risk
factors in arterial thrombosis.

Arterial thrombosis almost invariably occurs at sites of abnormalities in the
vessel wall.  Consistent progress is being made in identifying vascular factors
involved in regulating coagulant and adhesive activities of blood elements.  Yet,
the identification of the critical gene products in the vessel wall has only
begun.  An important clue is the occurrence of arterial thrombosis at particular
sites in the vasculature.  This suggests that the hemodynamics also play an
important role in influencing gene expression in the vessel and, consequently,
the predilection for arterial thrombosis.  Thus, the interplay between
hemodynamics and gene expression is another critical area for an understanding
of the predisposition towards arterial thrombosis.

Molecular genetic studies using the mouse are proving to be extremely valuable
in identifying candidates for genetic studies in humans.  In this regard, gene
knockout mouse models appear to represent an important breakthrough.  For
example, gene knockouts of a number of different natural anticoagulant
mechanisms, such as thrombomodulin, nitric oxide, tissue plasminogen activator,
and urokinase have demonstrated that significant amounts of fibrin are deposited
in arterial segments in an organ-specific fashion.  In the case of
thrombomodulin, fibrin deposition in arterial segments of the mouse heart results
in stress-induced myocardial infarction.  Furthermore, there are striking
similarities between phenotypes observed in the mouse knockout studies and
occurrence of arterial thrombotic phenotypes observed in humans.  For example,
the knockout of the endothelial nitric oxide synthase gene in the mouse resulted
in fibrin deposition within the blood vessels of the heart.  Interestingly, human
mutations in this enzyme are associated with ischemic heart disease in several
different ethnic populations.  Hence, these studies have provided a significant
number of candidate genes that appear to be involved in the initiation of
arterial thrombosis.  It is anticipated that additional studies with mice will
provide many more candidate genes as strategies are designed to develop genetic
defects in both time and location and to delete, mutate, or over express gene
products.  The Mouse Genome and the Rat Genome Projects are also generating tools
to identify the genetic bases of complex phenotypes that will provide additional
candidate genes.

There now exist exciting new opportunities for employing the knowledge gained
from the investigations and strategies described above to pinpoint the genetic
abnormalities in humans that lead to arterial thrombosis.  Given the available
biochemical assays of hypercoagulability, candidate genes, appropriate families,
the reagents, methods, and informational resources that are being generated by
the Human Genome Project, new analytical strategies, and more powerful study
designs, there is a strong rationale for supporting a significant effort to map
and identify the genes responsible for arterial thrombosis in humans and to
elucidate the complex interplay of genetic and environmental factors.  To this
end, it may be possible to use existing cell and DNA samples from already
completed American and European epidemiological and intervention trials concerned
with myocardial infarction, stroke, and peripheral vascular disease.  It would
also be of great interest to carry out similar studies in relatively young
individuals (below the age of 45) who exhibit arterial thrombosis with minimal
atherosclerotic disease.

Research using animal models also offer significant opportunities.  Animals can
be used to map and identify genetic variants responsible for arterial thrombosis. 
This information can be used for comparative mapping efforts in humans. 
Furthermore, animal models can be used to assess the biological mechanisms of
genetic variation that confers susceptibility to or protection from arterial
thrombosis.

An understanding of the basis for genetic susceptibility to the hypercoagulable
state and resultant arterial thrombosis would help identify individuals at risk
for developing disease before the manifestation of clinical symptoms. 
Furthermore, molecular genetic studies will help investigators develop measures
to characterize the prevalence of genetic variants associated with arterial
thrombosis at the population level.

Pinpointing the key genes and how they interact with each other and the
environment to produce arterial thrombosis would have a significant impact on
public health in a number of ways.  Such information will aid in identifying
individuals at greatest risk for developing arterial thrombosis and tailoring
prevention strategies, as well as providing information vital for the development
of safer and more effective prophylactic and therapeutic drugs.

Current data suggest that arterial thrombosis may represent a local imbalance
between procoagulant pathways, regulated by specific cellular circuits within a
particular organ, and natural anticoagulant mechanisms present on the blood
vessel wall.  If such is the case, down-regulation of the pro-coagulant circuits
or up-regulation of the anticoagulant mechanisms would result in a local
antithrombotic effect.  This would represent a new paradigm for prophylactic
therapy of arterial thrombosis, with a potentially dramatic reduction of bleeding
side effects which frequently occur with systemic anticoagulant therapy. Studies
are encouraged to develop approaches for identifying molecules that would help
in regulating these processes and elucidating their mechanisms of action.

Molecular genetic studies could ultimately have a substantial impact on the
prevention of arterial thrombotic disease.  A major challenge of the future will
be the development and implementation of effective preventive measures.  A better
understanding of disease mechanisms, which may result from molecular genetic
studies, should strengthen efforts at prevention by targeting those individuals
who are most likely to benefit from environmental and lifestyle modification and
by identifying individuals whose disease may not be improved through such
measures.

B.  Mechanism of Support

The mechanism available for support of applications in response to this
initiative is the collaborative R01.  In the case of collaborative R01 projects,
a group of investigators may submit simultaneously at least two research project
grants (R01s) with a common theme.  Collaborative R01 projects may be from a
single institution or several institutions, may include shared resources, and
must demonstrate the interdependence of the individual components. Applicants for
collaborative R01s may request funds to facilitate the logistics of
collaboration.  Such requests may include shared equipment or resources,
communication strategies, quality control activities, shared consultations or
seminars with experts complementing the project, or other mechanisms to cement
and enhance the relationships between investigators.  The justification for such
equipment or activities needs to be clearly made that they are designed to
promote collaborations and do not replicate ongoing activities or research.  Core
support for collaborative R01s is permissible and needs to be justified on the
basis of providing cohesion to collaborations or providing essential resources.

Upon initiation of the program, annual meetings will be held to encourage
exchange of information among investigators who participate in this program.  A
major goal of these meetings is to facilitate progress by providing a forum that
will lead to sharing ideas, technology, data, skills, and biological materials. 
Applicants must include travel funds that will allow principal investigators and
other key research scientists to participate in these meetings.

C.  Proposed Research

The goal of this initiative is to provide scientific underpinnings for rapid
advances in development of new therapeutic options in arterial thrombosis.  Three
critical areas are identified for emphasis:

1. Identification of genes involved in thrombosis in the arterial tree:

A key approach to identification of genes is genetic study of human populations
and pedigrees.  However, a common limiting factor in such studies is the
identification of candidate genes and the characterization of intermediate
phenotypes that are more easily tracked in positional cloning efforts. 
Innovative studies in animal models, or in vitro cell-based genetic approaches
are anticipated to be useful in pinpointing candidate genes.  Examination of
abundance of mRNA transcripts using array or related technologies are also
anticipated to provide rapid identification of candidate genes.

2. Validation of identified genes as molecular targets for arterial thrombosis:

Such studies are anticipated to make use of experimental alteration of the genome
of animal models such as mice.  In addition, other innovative approaches to test
the functionality of identified candidate genes in arterial thrombosis are
encouraged.

3.  Identification of local genes contributing to arterial thrombosis within the
brain:

The Blood-Brain-Barrier is an integral part of the pathology of ischemic stroke.
Investigating the molecular and cellular interactions at the blood-brain
interface is critical to increase our understanding of the pathobiological
processes of stroke.  Elucidating the involvement of brain-selective gene
expression on local arterial thrombosis can lead to stroke prevention and
neuroprotective strategies.

The identification of genes involved in thrombosis in the arterial vasculature
and a mechanistic analysis of how these genes contribute to hemostasis and to the
pathophysiology of arterial thrombosis in a vascular-bed and organ-specific
fashion will require the collaboration of investigators with expertise in many
fields, such as, genetics, biostatistics, clinical science, molecular biology,
biochemistry, physiology, bioinformatics, genomics, genotyping, and statistics. 
In addition, key aspects of infrastructure may also be supported, and might
include immortalization of cell lines to act as perpetual sources of DNA, the
banking of DNA, the development and maintenance of appropriate databases,
specialized equipment, and animal colonies.

It is important to emphasize that there are a variety of approaches to gene
mapping and identification and to the mechanistic analyses of the consequences
of genetic variation.  Therefore, a given strategy must be rigorously justified
and must demonstrate that all key personnel are involved in the formulation of
the rationale and approach.  For human genetic studies, as one example, the
applicants must carefully justify the study design, the phenotype, the human
population chosen for study, methodologies and technologies, statistical
analytical tools, and describe the limitations of the approaches.

Molecular genetics is a rapidly evolving field.  Hence, applications must include
a discussion of how its investigators will be poised to take advantage of
technical and methodological advances.  Although a key factor in the funding will
be the scientific and technical merit as judged through the peer review system,
willingness and ability to participate actively in a collaborative program will
also be a key factor in selecting applications for award.

Molecular genetic studies to map and identify genes responsible for arterial
thrombosis can involve human and/or animal studies.  Either approach will require
convincing justification of a phenotype reflective of the consequences of genetic
alteration on one or more factors involved in the etiology of arterial
thrombosis.  Genetic studies in humans may propose the use of existing tissue and
DNA samples from already completed epidemiologic and intervention trials or the
identification and study of new cohorts.  Animal studies to understand the
biological consequences of genetic variation might involve the development and
use of techniques to introduce and express new genetic information; development
and use of approaches to abolish or modify the expression of endogenous genes;
utilization of genetic ablation techniques to unravel the complex interactions
of systems comprised of multiple cell types; and so forth.

D.  Sharing Data and Biological Materials in Human Genetic Research

Timely sharing of information and materials will speed scientific discovery by
permitting researchers access to sufficiently large and well-characterized
resources as quickly as possible.  This sharing of materials and data, including
those that have not yet or may never be published, is essential to rapid progress
and will help to avoid unnecessary duplication of large data collections.  In
order to ensure the timely sharing of information and materials, applicants will
be requested to describe how, when, and in what manner data and materials will
be made available to the scientific community, with adequate safeguards to the
rights and interests of the participants for genetic research.  The initial
review group will comment on the proposed plan for sharing and data release.  The
adequacy of the plan and associated human subject protections will also be
considered by NIH staff as part of the criteria for award.  The proposed sharing
plan, after negotiation with the applicant when necessary, will be made a
condition of the award.

It is recognized that time may be required to verify the accuracy of data, to
perform initial analyses, and to protect intellectual property rights to ensure
that inventions, including therapeutic agents, are pursued and developed rapidly
for the benefit of the public.  Thus, a protected period - from the time data and
materials are collected to the time they are made available to other qualified
investigators - may be appropriate.  The onset and duration of the period will
vary, depending upon the nature of the research project.  Applicants must justify
the length of the protected period.

Where appropriate, grantees may work with the private sector to make unique
resources available to the larger biomedical research community at a reasonable
cost.  Applicants may request funds to defray the costs of sharing materials or
submitting data, with adequate justification.

EXCLUSIONS

This RFA is intended to support collaborative R01 research programs studying the
molecular genetic mechanisms of arterial thrombosis by mapping and identifying
genes that confer susceptibility, performing mechanistic studies to clarify the
role of specific genetic alterations, and to apply and further refine molecular
genetic methods and technologies directed to specific tissues at specific times
in development.  Genetic studies in humans may propose the use of existing tissue
and DNA samples from already completed epidemiologic and intervention trials or
the identification and study of new cohorts.  Large clinical trials will be
considered unresponsive to this initiative.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI and NINDS will sponsor periodic
meetings to encourage exchange of information among investigators who participate
in this program.  Applicants should include travel funds for a one day meeting
each year, most likely to be held in Bethesda, Maryland to the requested modules. 
Applicants should include a statement in their applications indicating their
willingness to participate in these meetings.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide to Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the
policy.

INCLUSION OF CHILDREN AS PARTICIPANTS IN THE RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the NIH
Policy and Guidelines on the Inclusion of Children as Participants in Research
Involving Human Subjects that was published in the NIH Guide for Grants and
Contracts, March 6, 1998, and is available at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by July 23, 1999, a letter of intent
that includes a descriptive title of the proposed research, the name, address,
and telephone number of the Principal Investigator, the identities of other key
personnel and participating institutions, and the number and title of the RFA in
response to which the application may be submitted.  Although a letter of intent
is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows staff to estimate
the potential review workload and to avoid conflict of interest in the review.

The letter of intent is to be mailed, or faxed, to:

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301)435-0266
FAX: (301)480-3541
Email: James_Scheirer@NIH.GOV

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants, with the modifications noted below.  These forms are available
at most institutional offices of sponsored research, and from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714,
email: GrantsInfo@nih.gov.

The RFA label found in the PHS 398 (rev. 4/98) application form must be affixed
to the bottom of the face page of the application. Failure to use this label
could result in delayed processing of the application such that it may not reach
the review committee in time for review.  In addition, the RFA title (Arterial
Thrombosis) and number (HL 99-015) must be typed on line 2 of the face page of
the application form and the YES box must be marked.

State on the face page, Title Line (line 1), of each application that the
submission is part of a "Collaborative R01."  The individual components and cores
must be submitted as one package accompanied by a cover letter that lists the
principal investigators of each R01.  Include this letter with each of the
individual R01s, and in each R01 list the collaborating projects and principal
investigators on page 2, under "Performance Sites".  In addition, the description
section for each R01 within a collaborative R01 should be the same and the
applicants should define how and why the individual participants propose to
collaborate.  Applicants should elaborate on the significance and nature of the
collaboration in an Introduction section of the "Research Plan" of each component
R01.

Sample budgets and justification page will be provided upon request or following
the submission of a letter of intent from Ms. Marie Willet at the address listed
below.

BUDGET INSTRUCTIONS

The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:

DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD

Do not complete Form Page 4 of the PHS 398 (rev 4/98).  It is not required nor
will it be accepted at the time of application.

BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT

Do not complete the categorical budget tables on page 5 of the PHS 398 (rev.
4/98) Form. Only the requested total direct costs line for each year must be
completed based on the number of $25,000 modules being requested.  Applicants may
not request a change in the amount of each module. A maximum of 32 modules
($800,000 direct costs) for the entire collaborative package, including cores,
per year may be requested .  Applicants may request up to five years of support
for this RFA.  Genetic studies in humans which propose the identification and
study of new cohorts may request up to seven years of support. Detailed
justification and time line for these studies should be included.  Direct cost
budgets will normally remain constant throughout the life of the project (i.e.,
the same number of modules requested for all budget periods).  Any necessary
escalation should be considered when determining the number of modules to be
requested.  However, in the event that the number of modules requested must
change in any future year due to the nature of the research proposed, appropriate
justification must be provided.  Total Direct Costs for the Entire Proposed
Project Period should be shown in the box provided.

BUDGET JUSTIFICATION

o  Budget justifications should be provided under "Justifications" on Form Page
5 of the PHS 398.

o  List the names, role on the project and proposed percent effort for all
project personnel (salaried or unsalaried)and provide a narrative justification
for each person based on his/her role on the project.

o  Identify all consultants by name and organizational affiliation and describe
the services to be performed.

o  Provide a general narrative justification for individual categories
(equipment, supplies, etc.) required to complete the work proposed.  More
detailed justifications should be provided for high cost items.  Any large one-
time purchases, such as large equipment requests, must be accommodated within
these limits.

CONSORTIUM/CONTRACTUAL COSTS

If collaborations or subcontracts are involved that require transfer of funds
from the grantee to other institutions, it is necessary to establish formal
subcontract agreements with each collaborating institution.  A letter of intent
from each collaborating institution should be submitted with the application. 
Only the percentage of the consortium/contractual TOTAL COSTS (direct and F&A)
relative to the total DIRECT COSTS of the overall project needs to be stated at
this time. The following example should be used to indicate the percentage cost
of the consortium, "The consortium agreement represents 27% of overall direct
costs requested in the first year." A budget justification for the consortium
should be provided as described in the "Budget  Justification" section above (no
Form Page 5 required for the consortium).  Please indicate whether the consortium
will be in place for the entire project period and identify any future year
changes in the percentage relative to the parent grant.

If there is a possibility for an award, the applicant will be requested to
identify actual direct and indirect costs for all years of the consortium. 
Please note that total subcontract costs need not be calculated in $25,000
modules. However, when subcontract funds are added to the parent grant budget,
the total direct cost amount must be included in the number of $25,000 modules
requested.

BIOGRAPHICAL SKETCH

A biographical sketch is required for all key personnel, following the modified
instructions below.  Do not exceed the two-page limit for each person.

o  Complete the educational block at the top of the form page;

o  List current position(s) and those previous positions directly relevant to the
application;

o  List selected peer-reviewed publications directly relevant to the proposed
project, with full citation;

o  The applicant has the option to provide information on research projects
completed and/or research grants participated in during the last five years that
are relevant to the proposed project.

OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). 
Selected other support information relevant to the proposed research may be
included in the Biographical Sketch as indicated above.  Complete Other Support
information will be requested by NHLBI or NINDS staff if there is a possibility
for an award.

CHECKLIST

No "Checklist" page is required as part of the initial application.  A completed
Checklist will be requested by NHLBI staff if there is a possibility for an
award.

The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.

Applications not conforming to these guidelines will be considered unresponsive
to this RFA and will be returned without further review.

Submit a signed typewritten original of the application and three signed,
photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application must be sent
to Dr. C. James Scheirer, at the address listed under LETTER OF INTENT.

Applications must be received by September 15, 1999 If an application is received
after that date, it will be returned to the applicant without review.  The Center
for Scientific Review (CSR) will not accept any application in response to this
RFA that is essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The CSR will not accept any
application that is essentially the same as one already reviewed.  This does not
preclude the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR, and
responsiveness by NHLBI and NINDS.  Incomplete and/or non-responsive applications
will be returned to the applicant without further consideration.  Remaining
applications may be subjected to a streamlined review process by a Special
Emphasis Panel convened by NHLBI Scientific Review Office to determine their
scientific merit relative to other applications received in response to the RFA.
The roster of reviewers for the RFA will be available on the NHLBI home page
approximately four weeks prior to the scheduled review date. Applications
determined to be meritorious will be evaluated for scientific and technical merit
by the review committee, be discussed and receive a priority score.  All other
applications will not be discussed or scored. The initial review group will
evaluate all applications as individual investigator-initiated grant
applications.  Additionally, the IRG will consider in their evaluation the
overall strength and likelihood of effective collaboration of each collaborative
program. Each R01 will receive a priority score. Secondary review of the
applications will be conducted by the National Heart, Lung, and Blood Advisory
Council (NHLBAC) and the National Advisory Neurological Disorders and Stroke
Council (NANDS).

Review Criteria:

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

1) Significance
Does this study address an important problem? If the aims of the application are
achieved, how will scientific knowledge be advanced? What will be the effect of
these studies on the concepts or methods that drive this field?

2) Approach
Are the conceptual framework, design, methods, and analyses adequately developed,
well integrated, and appropriate to the aims of the project? Does the applicant
acknowledge potential problem areas and consider alternative tactics?

3) Innovation
Does the project employ novel concepts, approaches or method? Are the aims
original and innovative? Does the project challenge existing paradigms or develop
new methodologies or technologies?

4) Investigator
Is the investigator appropriately trained and well suited to carry out this work?
Is the work proposed appropriate to the experience level of the principal
investigator and other researchers (if an)?

5) Environment
Does the scientific environment in which the work will be done contribute to the
probability of success? Do the proposed experiments take advantage of unique
features of the scientific environment or employ useful collaborative
arrangements? Is there evidence of institutional support?

6) Collaboration
What are the likelihood of effective collaboration among the investigators, and
the likelihood of success of the research objectives proposed?

The personnel category will be reviewed for appropriate staffing based on the
requested percent effort.  The direct costs budget request will be reviewed for
consistency with the proposed methods and specific aims.  Any budgetary
adjustments recommended by the reviewers will be in $25,000 modules.  The
duration of support will be reviewed to determine if it is appropriate to ensure
successful completion of the requested scope of the project.

AWARD CRITERIA

Applications will receive a secondary level of review by National Heart, Lung,
and Blood Advisory Council (NHLBAC) and by the National Institute of Neurological
Disorders and Stroke Advisory council (NANDS) in May 2000. The earliest
anticipated date of award is July 2000. Applicants should be aware that, in
addition to scientific merit, program priorities and program balance, the total
costs of the proposed project and the availability of funds will be considered
by NHLBI and by NINDS staff as well as NHLBAC and the NANDS in making funding
recommendations.  The Institute may fund individual applications based on a
number of considerations, the most important of which are based on their
scientific merit and their importance in meeting the objectives of the RFA.  In
addition, both Institutes  appreciate the value of complementary funding from
other public and private sources including foundations and industrial concerns.

SCHEDULE

Letter of Intent Receipt Date:                August 16, 1999
Application Receipt Date:                     September 15, 1999
Review by NHLBI and NINDS Advisory Councils:  May 2000
Anticipated Award Date:                       August 2000

INQUIRIES

Inquiries concerning this RFA are encouraged.  Potential applicants should
request a copy of the full RFA, which will include sample budget pages. The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding programmatic issues to:

Carol H. Letendre, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10142
Bethesda, MD 20892-7950
Telephone: (301) 435-0080, FAX: (301) 480-0867
Email:  letendrc@gwgate.nhlbi.nih.gov

Sonia Skarlatos, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10186
Bethesda, MD  20892-7956
Telephone:  (301) 435-0550, FAX:  (301) 480-2848
Email:  skarlats@gwgate.nhlbi.nih.gov

Thomas P. Jacobs, Ph.D.
Division of Stroke, Trauma, and Neurodegenerative Diseases
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., suite 2209
Bethesda, MD 20892
Telephone: (301) 496-4226, FAX: (301) 480-1080
Email:  tj12g@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Marie Willet
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7156
Bethesda, MD  20892-7926
Telephone:  (301)435-0144; FAX:  (301)480-3310
Email: willetm@gwgate.nhlbi.nih.gov

Ms. Kathleen Howe
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuro-Science Center
6001 Executive Boulevard
Bethesda, MD 20892-9537
Telephone: (301) 496-7392; FAX: (301) 402-0219
Email: kh52x@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.839 and 93.854.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law
99-158, 42 USC 241 and 285) and administered under PHS grants' policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject
to the intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.  In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in
certain facilities (or in some cases, any portion of a facility) in which regular
or routine education, library, day care, health care or early childhood
development services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the American
people.



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